TCR-independent CD137 (4-1BB) signaling promotes CD8+-exhausted T cell proliferation and terminal differentiation

作者：Andrea Pichler, Nadège Carrié, Marine Cuisinier, Samira Ghazali, Allison Voisin, Pierre‐Paul Axisa, Marie Tosolini, Céline Mazzotti, Dominic P. Golec, Sabrina Mahéo, Laura Do Souto, Rüçhan Ekren, Eve Blanquart, L Lemaître, Virginie Féliu, Marie-Véronique Joubert, Jennifer L. Cannons, Camille Guillerey, Hervé Avet‐Loiseau, Tania H. Watts, Benoı̂t L. Salomon, Olivier Joffre, Yenkel Grinberg‐Bleyer, Pamela L Schwartzberg, Liliana E. Lucca, Ludovic Martinet · 发表于：Immunity · 年份：2023 · DOI：10.1016/j.immuni.2023.06.007 · 被引用次数：117 · 研究领域：CAR-T cell therapy research、Immune Cell Function and Interaction、Cancer Immunotherapy and Biomarkers

CD137 (4-1BB)-activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by CD137 and its role in cancer immune surveillance remain unresolved. Using T cell-specific deletion and agonist antibodies, we found that CD137 modulates tumor infiltration of CD8 + -exhausted T (Tex) cells expressing PD1, Lag-3, and Tim-3 inhibitory receptors. T cell-intrinsic, TCR-independent CD137 signaling stimulated the proliferation and the terminal differentiation of Tex precursor cells through a mechanism involving the RelA and cRel canonical NF-κB subunits and Tox-dependent chromatin remodeling. While Tex cell accumulation induced by prophylactic CD137 agonists favored tumor growth, anti-PD1 efficacy was improved with subsequent CD137 stimulation in pre-clinical mouse models. Better understanding of T cell exhaustion has crucial implications for the treatment of cancer and infectious diseases. Our results identify CD137 as a critical regulator of Tex cell expansion and differentiation that holds potential for broad therapeutic applications.